Natural killer (NK) cells participate in the innate immune response against pathogens and tumors. There is growing evidence that they are involved in allograft rejection and possibly in certain autoimmune diseases. The receptors on NK cells responsible for their activation are only now being appreciated. One of these receptors, NKG2D, has been implicated in the ability of NK cells to kill certain tumors and virus-infected cells. NKG2D is present on all NK cells, CDS+T cells, gammadelta-TcR + T cells and some activated macrophages. Recently, we and others cloned a family of mouse genes, designated RAE-1, encoding MHC class I-like proteins that bind with high affinity to mouse NKG2D. Human orthologs of the RAE-1 genes (designated as either ULBP or RAE-1-like genes) have been identified and the proteins encoded by these genes are recognized by the human NKG2D receptor. In humans, the NKG2D receptor also recognizes MICA and MICB, polymorphic MHC class I antigens that are induced by stress, transformation and viral infection. Emerging evidence suggests that the RAE-1 and MIC glycoproteins may serve to trigger the innate immune responses mediated by NK cells and gammadelta-TcR +T cells and function to co-stimulate antigen-specific responses by CD8 + cytotoxic T lymphocytes. We propose to investigate the RAE-1 family of genes and determine their role in innate and adaptive immune responses. The specific aims of this program are: 1) to determine whether the RAE-1 genes are polymorphic, analyze their expression and determine if they elicit allogeneic responses, 2) to establish the relevance of induction of the RAE-1 molecules during viral infection, to determine how the human CMV UL 16 protein and potentially other viral proteins interfere with RAE-1, and to evaluate whether viruses other than HCMV induce the RAE-1 genes, and 3) to evaluate the mechanisms responsible for the induction of the RAE-1 genes in normal cells. The overall objective of this project is to understand both the beneficial and potentially adverse functions of the RAE- 1 family of antigens in innate and adaptive immune responses.